ALDH1A3 Gene
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ALDH1A3 — Aldehyde Dehydrogenase 1 Family Member A3</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ALDH1A3</td>
</tr>
<tr>
<td class="label">Gene Name</td>
<td>Aldehyde Dehydrogenase 1 Family Member A3</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>ALDH1A3, RALDH3, ALDH6</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>15q26.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>220</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P47820</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000184254</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>610463</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Aldehyde dehydrogenase (ALDH) family</td>
</tr>
<tr>
<td class="label">Substrate</td>
<td>Km (μM)</td>
</tr>
<tr>
<td class="label">All-trans-retinal</td>
<td>0.5-2.0</td>
</tr>
<tr>
<td class="label">4-HNE</td>
<td>10-50</td>
</tr>
<tr>
<td class="label">Malondialdehyde</td>
<td>20-100</td>
</tr>
<tr>
<td class="label">9-cis-retinal</td>
<td>1-5</td>
</tr>
<tr>
<td class="label">Protein/Pathway</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">NAD(P)+</td>
<td>Cofactor</td>
</tr>
<tr>
<td class="label">All-trans-retinal</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">4-HNE</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">RARα/β/γ</td>
<td>RA product</td>
</tr>
<tr>
<td class="label">RXR</td>
<td>Heterodimer partner</td>
</tr>
<tr>
<td class="label">CRBP (cellular retinol-binding protein)</td>
<td>Binding</td>
</tr>
<tr>
<td class="label">ADH1A</td>
<td>Parallel enzyme</td>
</tr>
<tr>
<td class="label">ALDH1A1</td>
<td>Homolog</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">16 edges</a></td>
</tr>
</table>
Overview
Mermaid diagram (expand to render)
ALDH1A3 (Aldehyde Dehydrogenase 1 Family Member A3), also known as ALDH1A3 or RALDH3, encodes a crucial enzyme in the aldehyde dehydrogenase family that catalyzes the oxidation of retinaldehyde to retinoic acid (RA), a potent signaling molecule essential for development, cell differentiation, and tissue homeostasis["@yoshida2013"][@vasiliou2000]. This gene has garnered significant attention in neuroscience due to its dual roles in retinoid metabolism and aldehyde detoxification, both of which are critical processes in normal brain function and implicated in neurodegenerative disease pathogenesis.
The ALDH1A3 enzyme belongs to the ALDH1 family, which consists of cytosolic enzymes with high affinity for all-trans-retinaldehyde (RAL), the immediate precursor of all-trans-retinoic acid (ATRA). Unlike other ALDH1A isoforms (ALDH1A1 and ALDH1A2), ALDH1A3 exhibits distinct expression patterns and substrate preferences that make it particularly important in specific brain regions and during particular developmental stages["@kopp2014"].
Beyond its well-established role in retinoid metabolism, ALDH1A3 has emerged as an important player in neuroprotection through its involvement in detoxifying aldehydes that accumulate under conditions of oxidative stress—a hallmark of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and various neurological disorders["@hernandez2015"]. The enzyme's ability to convert toxic aldehydes like 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) into non-toxic carboxylic acids provides a crucial defense mechanism against oxidative damage in neurons and glial cells.
Protein Structure and Function
Enzyme Classification and Structure
ALDH1A3 is a member of the ALDH superfamily, which encompasses enzymes that catalyze the NAD(P)-dependent oxidation of aldehydes to carboxylic acids. The ALDH1A3 protein consists of multiple structural domains:
Nucleotide-binding domain (NBD): Contains the NAD(P) binding site (TIGGHAGQ motif)
Catalytic domain: Houses the active site with a conserved cysteine residue (Cys302) essential for catalysis
Oligomerization domain: Mediates formation of the functional tetramerThe enzyme functions as a homotetramer, with each subunit comprising approximately 512 amino acids. The quaternary structure is essential for enzyme stability and activity.
Catalytic Activity
ALDH1A3 catalyzes the following principal reactions:
All-trans-retinaldehyde (RAL) → All-trans-retinoic acid (RA)
- Primary enzymatic function
- Produces the morphogen retinoic acid
- Essential for development and differentiation
9-cis-retinaldehyde → 9-cis-retinoic acid
- Though ALDH1A3 preferentially acts on all-trans isoforms
- Contributes to 9-cis-RA pool under specific conditions
Aldehyde Detoxification
4-Hydroxynonenal (4-HNE) → 4-HNE acid
- Major lipid peroxidation product
- Highly toxic to neurons
- ALDH1A3 provides crucial detoxification
Malondialdehyde (MDA) → Malonic acid
- Another lipid peroxidation product
- Contributes to oxidative damage
- ALDH1A3 contributes to clearance
Other aldehydes: Propionaldehyde, hexanal, acetaldehydeSubstrate Specificity
Expression Pattern in the Brain
Regional Distribution
ALDH1A3 exhibits a distinctive expression pattern in the central nervous system[@yang2018]:
- Retina: Highest expression in the retinal pigment epithelium and photoreceptor cells
- Hippocampus: Moderate expression in CA1-CA3 regions and dentate gyrus
- Cortex: Expression across all cortical layers, highest in layer II/III
- Oligodendrocyte lineage: High expression in developing oligodendrocytes
- Substantia nigra: Present in dopaminergic neurons
- Cerebellum: Expression in Purkinje cells and granule cells
Cellular Distribution
- [Neurons](/entities/neurons): Expression in excitatory and inhibitory neurons
- [Astrocytes](/entities/astrocytes): Moderate expression, varies by brain region
- Oligodendrocytes: High expression during development and in white matter
- Neural progenitor cells: Expression declines with differentiation
- Microglia: Lower expression under normal conditions
Developmental Regulation
- Embryonic development: High expression in neural tube and developing brain
- Postnatal period: Expression decreases but remains in specific regions
- Adult brain: Maintained expression in neurogenic niches (hippocampus, subventricular zone)
Role in Neurodegenerative Diseases
Alzheimer's Disease
ALDH1A3 plays complex roles in AD pathogenesis[@kong2019]:
Retinoid Signaling Dysregulation
- RA levels are reduced in AD brains
- ALDH1A3 deficiency contributes to impaired neurogenesis
- Retinoid signaling deficits affect synaptic plasticity
- Loss of RA-mediated neuroprotection
Oxidative Stress
- 4-HNE accumulation in AD brains
- ALDH1A3 activity declines with age and AD
- Impaired detoxification exacerbates oxidative damage
- Creates feed-forward cycle of neurodegeneration
Neurogenesis
- ALDH1A3 promotes neural stem cell differentiation
- Deficiency reduces hippocampal neurogenesis
- Impairs cognitive function
- Therapeutic potential of RA supplementation
Therapeutic Implications
- RA treatment shows benefit in AD models
- ALDH1A3 overexpression enhances neurogenesis
- Combination with other approaches
- Biomarker potential
Parkinson's Disease
ALDH1A3 dysfunction contributes to PD through multiple mechanisms[@chen2022]:
Dopaminergic Neuron Vulnerability
- ALDH1A3 expression in substantia nigra dopaminergic neurons
- Loss of ALDH1A3 increases vulnerability to toxins
- 4-HNE accumulation in PD brains
- Impaired detoxification contributes to cell death
Retinoid Signaling
- RA is essential for dopaminergic neuron development
- RA deficiency affects neuron maintenance
- Retinoic acid signaling in PD models
Neuroinflammation
- ALDH1A3 in glial cells modulates inflammation
- Retinoid signaling affects microglial activation
- Potential for therapeutic modulation
Glioma and Brain Tumors
ALDH1A3 has been extensively studied in cancer[@patel2017][@kim2017][@kong2020]:
Cancer Stem Cells
- ALDH1A3 is a marker for glioma stem cells (GSCs)
- High ALDH1A3 expression correlates with poor prognosis
- Promotes tumor initiation and self-renewal
- Enhances resistance to therapy
Tumorigenesis
- ALDH1A3 promotes glioma cell proliferation
- RA signaling supports tumor growth
- Epithelial-mesenchymal transition (EMT)
- Angiogenesis promotion
Therapeutic Targeting
- ALDH1A3 knockdown reduces tumor growth
- Inhibitors under development
- Combination with standard therapies
- Promising target for glioblastoma
Other Neurological Conditions
Raine Syndrome
ALDH1A3 mutations cause this rare autosomal recessive disorder[@sack2016]:
- Brain malformations (lissencephaly, polymicrogyria)
- Facial dysmorphism
- Limb abnormalities
- Severe neurological impairment
Neuroblastoma
ALDH1A3 is expressed in neural crest-derived tumors[@sturm2012]:
- Associated with poor differentiation
- Potential therapeutic target
- Developmental link to neural crest
Epilepsy
- ALDH1A3 mutations associated with epilepsy
- Retinoid signaling in seizure susceptibility
- Oxidative stress in epileptogenesis
Biological Functions Beyond Neurodegeneration
Retinoid Signaling
Development
- Essential for brain development
- Pattern formation in neural tube
- Segmentation and regionalization
- Axon guidance
Differentiation
- Promotes neuronal differentiation
- Supports oligodendrocyte maturation
- Astrocyte fate specification
- Synaptogenesis
Plasticity
- Synaptic plasticity modulation
- Memory formation
- Visual system function
- Circuit refinement
Oxidative Stress Defense
Neuroprotection
- Direct detoxification of lipid peroxidation products
- Maintains cellular redox balance
- Protects against environmental toxins
- Supports neuronal survival
Signaling
- 4-HNE as a signaling molecule (at low levels)
- RA as a neuroprotective factor
- Cross-talk with antioxidant pathways
Interacting Partners and Pathways
Therapeutic Strategies
Targeting ALDH1A3
In Neurodegeneration
Retinoic acid supplementation: RA or RA analogs
Gene therapy: AAV-mediated ALDH1A3 expression
Small molecule activators: Enhance ALDH1A3 activity
Antioxidant approaches: Reduce aldehyde burdenIn Cancer
ALDH1A3 inhibition: Direct enzyme inhibitors
Differentiation therapy: RA to promote differentiation
Combination therapies: With chemotherapy/radiation
Targeted delivery: Tumor-specific deliveryChallenges
- Blood-brain barrier penetration
- Off-target effects of RA
- Optimal dosing strategies
- Disease-stage specific effects
Animal Models
- ALDH1A3 knockout mice: Embryonic lethal (some lines)
- Conditional knockouts: Brain-specific deletion
- Transgenic overexpression: Specific models
- Humanized models: For drug testing
Cell Models
- Primary neurons and astrocytes
- iPSC-derived neural cells
- Glioma stem cells
- Organoid models
- Activators: RA, synthetic retinoids
- Inhibitors: Disulfiram (non-specific), specific inhibitors in development
- Substrates: Fluorescent aldehyde substrates
- [Retinoic Acid Signaling](/mechanisms/retinoic-acid-signaling) - Complete RA pathway
- [Aldehyde Dehydrogenase](/enzymes/aldehyde-dehydrogenase) - Enzyme family
- [Oxidative Stress](/mechanisms/oxidative-stress) - ROS and damage
- [Neurogenesis](/mechanisms/neurogenesis) - Neural stem cells
- [Retinoid Metabolism](/mechanisms/retinoid-metabolism) - Vitamin A pathway
- [Alzheimer's Disease](/diseases/alzheimers-disease) - AD overview
- [Parkinson's Disease](/diseases/parkinsons-disease) - PD overview
- [Glioma](/diseases/glioma) - Brain tumor
- [Retina](/brain-regions/retina) - Visual system
- [Hippocampus](/brain-regions/hippocampus) - Memory
- [ALDH1A1](/entities/aldh1a1) - ALDH1 isoform
- [ALDH1A2](/entities/aldh1a2) - ALDH1 isoform
- [RARA](/entities/rara) - Retinoic acid receptor
- [CRBP](/entities/crbp) - Cellular retinol binding
Future Directions and Research Gaps
Current Understanding
- ALDH1A3 roles in neurodegeneration are emerging
- Cancer stem cell functions well-characterized
- Retinoid metabolism pathway established
Unmet Needs
- Selective ALDH1A3 modulators with brain penetration
- Understanding cell-type-specific functions
- Disease-stage specific effects
- Biomarker development
Emerging Areas
Single-cell analysis: Cell-type-specific ALDH1A3 functions
Epigenetic regulation: Transcriptional control of ALDH1A3
Spatial transcriptomics: Regional expression patterns
Therapeutic development: Brain-penetrant small moleculesSee Also
- [Retinoic Acid Signaling](/mechanisms/retinoic-acid-signaling) - Complete RA signaling overview
- [Aldehyde Dehydrogenase](/enzymes/aldehyde-dehydrogenase) - Enzyme family overview
- [Oxidative Stress and Neurodegeneration](/mechanisms/oxidative-stress) - ROS in disease
- [Neurogenesis in the Adult Brain](/mechanisms/neurogenesis) - Neural stem cells
- [Alzheimer's Disease](/diseases/alzheimers-disease) - Comprehensive AD overview
- [Parkinson's Disease](/diseases/parkinsons-disease) - Comprehensive PD overview
- [Glioma](/diseases/glioma) - Brain tumor overview
- [Retinal Development](/brain-regions/retina) - Visual system development
- [Hippocampal Neurogenesis](/brain-regions/hippocampus) - Memory and neurogenesis
External Links
- [NCBI Gene - ALDH1A3](https://www.ncbi.nlm.nih.gov/gene/220)
- [UniProt - P47820](https://www.uniprot.org/uniprot/P47820)
- [Ensembl - ENSG00000184254](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000184254)
- [OMIM - 610463](https://www.omim.org/entry/610463)
- [GeneCards - ALDH1A3](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ALDH1A3)
References
[Yoshida A et al, Human aldehyde dehydrogenase gene family (2013)](https://pubmed.ncbi.nlm.nih.gov/23533239/)
[Marcato P et al, ALDH1A3 as a cancer stem cell marker (2011)](https://pubmed.ncbi.nlm.nih.gov/21889922/)
[Sack MN et al, ALDH1A3 mutations cause autosomal recessive syndrome (2016)](https://pubmed.ncbi.nlm.nih.gov/26969326/)
[Moore R et al, ALDH1A3 promotes neurogenesis in adult brain (2018)](https://pubmed.ncbi.nlm.nih.gov/29628893/)
[Vasiliou V et al, Role of aldehyde dehydrogenases in cellular responses to oxidative stress (2000)](https://pubmed.ncbi.nlm.nih.gov/10817650/)
[Kopp LM et al, Retinoic acid signaling in neural stem cells (2014)](https://pubmed.ncbi.nlm.nih.gov/25480377/)
[Patel M et al, Targeting ALDH1A3 in glioblastoma (2017)](https://pubmed.ncbi.nlm.nih.gov/28445756/)
[Hernandez GE et al, Aldehyde dehydrogenases in cell defense and disease (2015)](https://pubmed.ncbi.nlm.nih.gov/25712741/)
[Kong G et al, ALDH1A3 promotes neuronal differentiation in AD model (2019)](https://pubmed.ncbi.nlm.nih.gov/30636521/)
[Yang L et al, ALDH1A3 in retinal development (2018)](https://pubmed.ncbi.nlm.nih.gov/29272454/)
[Chang CJ et al, ALDH1A3 isoform overexpressed in brain tumors (2015)](https://pubmed.ncbi.nlm.nih.gov/26245967/)
[Du Z et al, ALDH1A3 deficiency impairs neurogenesis (2020)](https://pubmed.ncbi.nlm.nih.gov/32822574/)
[Kim J et al, ALDH1A3 as marker of glioma stem cells (2017)](https://pubmed.ncbi.nlm.nih.gov/28855252/)
[Sturm D et al, Novel ALDH1A3 mutations in neuroblastoma (2012)](https://pubmed.ncbi.nlm.nih.gov/23103626/)
[Chen X et al, Retinoic acid signaling in neurodegenerative diseases (2021)](https://pubmed.ncbi.nlm.nih.gov/33581121/)
[Lee K et al, ALDH1A3 polymorphisms and neurodegenerative disease risk (2022)](https://pubmed.ncbi.nlm.nih.gov/35041356/)
[Zhang W et al, ALDH1A3 protects against oxidative stress (2019)](https://pubmed.ncbi.nlm.nih.gov/31104589/)
[Kong G et al, Targeting ALDH1A3 for glioblastoma treatment (2020)](https://pubmed.ncbi.nlm.nih.gov/32812837/)
[Wang J et al, ALDH1A3 in neural stem cell differentiation (2021)](https://pubmed.ncbi.nlm.nih.gov/33612687/)
[Chen J et al, ALDH1A3 in dopaminergic neuron survival in PD (2022)](https://pubmed.ncbi.nlm.nih.gov/34954723/)
[Sun W et al, ALDH1A3 in synaptic plasticity and memory (2023)](https://pubmed.ncbi.nlm.nih.gov/36753618/)Pathway Diagram
The following diagram shows the key molecular relationships involving ALDH1A3 — Aldehyde Dehydrogenase 1 Family Member A3 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)